Schleifer Charles H, Chang Sarah E, Amir Carolyn M, O'Hora Kathleen P, Fung Hoki, Kang Jee Won D, Kushan-Wells Leila, Daly Eileen, Di Fabio Fabio, Frascarelli Marianna, Gudbrandsen Maria, Kates Wendy R, Murphy Declan, Addington Jean, Anticevic Alan, Cadenhead Kristin S, Cannon Tyrone D, Cornblatt Barbara A, Keshavan Matcheri, Mathalon Daniel H, Perkins Diana O, Stone William S, Walker Elaine, Woods Scott W, Uddin Lucina Q, Kumar Kuldeep, Hoftman Gil D, Bearden Carrie E
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California.
Department of Psychology, University of California, Los Angeles, Los Angeles, California.
Biol Psychiatry. 2025 Jan 15;97(2):178-187. doi: 10.1016/j.biopsych.2024.08.010. Epub 2024 Aug 23.
22q11.2 deletion syndrome (22qDel) is a copy number variant that is associated with psychosis and other neurodevelopmental disorders. Adolescents who are at clinical high risk for psychosis (CHR) are identified based on the presence of subthreshold psychosis symptoms. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped the results to biological pathways.
We analyzed 2 large multisite cohorts with resting-state functional magnetic resonance imaging data: 1) a 22qDel cohort (n = 164, 47% female) and typically developing (TD) control participants (n = 134, 56% female); and 2) a cohort of CHR individuals (n = 240, 41% female) and TD control participants (n = 149, 46% female) from the NAPLS-2 (North American Prodrome Longitudinal Study-2). We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions and tested case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation.
BSV, LC, and GBC were significantly disrupted in individuals with 22qDel compared with TD control participants (false discovery rate-corrected q < .05). Spatial maps of BSV and LC differences were highly correlated with each other, unlike GBC. In the CHR group, only LC was significantly altered versus the control group, with a different spatial pattern than the 22qDel group. Group differences mapped onto biological gradients, with 22qDel effects being strongest in regions with high predicted blood flow and metabolism.
22qDel carriers and CHR individuals exhibited different effects on functional magnetic resonance imaging temporal variability and multiscale functional connectivity. In 22qDel carriers, strong and convergent disruptions in BSV and LC that were not seen in CHR individuals suggest distinct functional brain alterations.
22q11.2 缺失综合征（22qDel）是一种拷贝数变异，与精神病及其他神经发育障碍相关。处于临床精神病高危状态（CHR）的青少年是根据阈下精神病症状的存在来确定的。这些不同的高危人群是否存在共同的神经基质尚不清楚。我们比较了 22qDel 和 CHR 队列中的脑功能测量指标，并将结果映射到生物通路。
我们分析了 2 个大型多中心队列的静息态功能磁共振成像数据：1）一个 22qDel 队列（n = 164，47%为女性）和正常发育（TD）对照参与者（n = 134，56%为女性）；2）来自 NAPLS - 2（北美前驱期纵向研究 - 2）的 CHR 个体队列（n = 240，41%为女性）和 TD 对照参与者（n = 149，46%为女性）。我们计算了整个皮质区域的全脑连通性（GBC）、局部连通性（LC）和脑信号变异性（BSV），并分别测试了 22qDel 和 CHR 的病例对照差异。使用保留自相关的置换将组间差异图与已发表的脑图谱相关联。
与 TD 对照参与者相比，22qDel 个体的 BSV、LC 和 GBC 显著受损（错误发现率校正后的 q <.05）。与 GBC 不同，BSV 和 LC 差异的空间图彼此高度相关。在 CHR 组中，与对照组相比只有 LC 有显著改变，其空间模式与 22qDel 组不同。组间差异映射到生物梯度上，22qDel 的影响在预测血流和代谢较高的区域最强。
22qDel 携带者和 CHR 个体对功能磁共振成像时间变异性和多尺度功能连通性表现出不同的影响。在 22qDel 携带者中，BSV 和 LC 出现强烈且趋同的破坏，而 CHR 个体中未出现，这表明存在不同的脑功能改变。
